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Phytomedicine. 2018 Feb 1;40:148-157. doi: 10.1016/j.phymed.2018.01.012. Epub 2018 Jan 31.

Piscroside C inhibits TNF-α/NF-κB pathway by the suppression of PKCδ activity for TNF-RSC formation in human airway epithelial cells.

Author information

1
Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju-si, Cheongju-si 28116, Republic of Korea.
2
Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju-si, Cheongju-si 28116, Republic of Korea; Department of Biological Sciences, College of Bioscience and Biotechnology, Chungnam National University, Daejeon, Republic of Korea.
3
Department of Biological Sciences, College of Bioscience and Biotechnology, Chungnam National University, Daejeon, Republic of Korea.
4
Korean Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
5
Department of Anatomy & Cell biology, College of Medicine, Chungnam National University, 266, Munhwa-Ro, Daejeon 35015, Republic of Korea. Electronic address: mogwai@cnu.ac.kr.
6
Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju-si, Cheongju-si 28116, Republic of Korea. Electronic address: seiryang@kribb.re.kr.

Abstract

BACKGROUND:

Piscroside C, isolated from Pseudolysimachion rotundum var. subintegrum, is a novel iridoid glycoside with therapeutic efficacy in a mouse model of chronic obstructive pulmonary disease (COPD). Piscroside C has been reported as a constituent of YPL-001 (under Phase 2a study, ClinicalTrials.gov identifier NCT02272634).

PURPOSE:

To investigate the mechanisms behind piscroside C therapeutic effects on COPD in human airway epithelial NCI-H292 cells.

METHODS:

We tested if piscroside C effectively suppresses MUC5AC gene expression and TNF-RSC/IKK/NF-κB cascades in TNF-α-stimulated NCI-H292 cells by employing, reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, luciferase reporter assays, chromatin immunoprecipitation assays and immunoprecipitation.

RESULTS:

Piscroside C markedly suppressed the expression of TNF-α-induced MUC5AC mucus protein by inhibiting the transcriptional activity of NF-κB in NCI-H292 cells. Indeed, piscroside C negatively regulated the function of TNF receptor 1 signaling complex (TNF-RSC, an upstream regulator of the NF-κB pathway) without affecting its extracellular interaction with the TNF-α ligand. This inhibitory effect by piscroside C is mediated by the inactivation of protein kinase C (PKC), an essential regulator of TNF-RSC. PKC inactivation by piscroside C results in decreased PKCδ binding to a TRAF2 subunit of TNF-RSC and subsequent reduced IKK phosphorylation, resulting in NF-κB inactivation.

CONCLUSION:

We propose that piscroside C is a promising therapeutic constituent of YPL-001 through its inhibition of PKCδ activity in the TNF-RSC/IKK/NF-κB/MUC5AC signaling cascade.

KEYWORDS:

Chronic obstructive pulmonary disease; Mucin 5AC; NF-κB; Piscroside C; Protein kinase C; TNF-α

PMID:
29496167
DOI:
10.1016/j.phymed.2018.01.012
[Indexed for MEDLINE]

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